Mutation in the gene encoding lysosomal acid phosphatase (Acp2) causes cerebellum and skin malformation in mouse
- 276 Downloads
We report a novel spontaneous mutation named nax in mice, which exhibit delayed hair appearance and ataxia in a homozygote state. Histological analyses of nax brain revealed an overall impairment of the cerebellar cortex. The classical cortical cytoarchitecture was disrupted, the inner granule cell layer was not obvious, the Purkinje cells were not aligned as a Purkinje cell layer, and Bergmann glias did not span the molecular layer. Furthermore, histological analyses of skin showed that the hair follicles were also abnormal. We mapped the nax locus between marker D2Mit158 and D2Mit100 within a region of 800 kb in the middle of chromosome 2 and identified a missense mutation (Gly244Glu) in Acp2, a lysosomal monoesterase. The Glu244 mutation does not affect the stability of the Acp2 transcript, however it renders the enzyme inactive. Ultrastructural analysis of nax cerebellum showed lysosomal storage bodies in nucleated cells, suggesting progressive degeneration as the underlying mechanism. Identification of Acp2 as the gene mutated in nax mice provides a valuable model system for studying the role of Acp2 in cerebellum and skin homeostasis.
KeywordsMutant mouse strain Genetic linkage Cerebellum Hair follicle Lysosomal storage diseases
This work was funded by the Deutsche Forschungsgemeinschaft through the DFG-Research Center for Molecular Physiology of the Brain to W.E. and M.R. The authors would like to thank S. Zimmermann for operational help, M. Wahl for assistance with structural biology programs, and K. von Figura for useful discussions and helping us with Acp2 enzymatic assay. A. Eberwein, M. Moeschner, and M. Steckel for technical assistance, and our animal housekeepers for breeding and maintaining these mice.
Table S1 Summary of genes reported in nax locus
- 6.De Duve C (1959) Subcellular particles. In: Hayashi T (ed) Ronald Press, pp 128–159Google Scholar
- 12.Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New YorkGoogle Scholar
- 21.Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna I, Pant HC, Brady RO, Martin LJ, Kulkarni AB (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci U S A 93:11173–11178CrossRefPubMedGoogle Scholar
- 26.Roth W, Deussing J, Botchkarev VA, Pauly-Evers M, Saftig P, Hafner A, Schmidt P, Schmahl W, Scherer J, Anton-Lamprecht I, Figura K von, Paus R, Peters C (2000) Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J 14:2075–2086CrossRefPubMedGoogle Scholar
- 27.Suter A, Everts V, Boyde A, Jones SJ, Lullmann-Rauch R, Hartmann D, Hayman AR, Cox TM, Evans MJ, Meister T, Figura K von, Saftig P (2001) Overlapping functions of lysosomal acid phosphatase (LAP) and tartrate-resistant acid phosphatase (Acp5) revealed by doubly deficient mice. Development 128:4899–4910PubMedGoogle Scholar